Process for the preparation of imidazole compounds

ABSTRACT

A process for the preparation of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone which comprises reacting 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone with a C 6-8 alkyllithium compound, 1-methylimidazole and a tri(C 4-6 alkyl)silyl halide to obtain better yields of the above product.

[0001] The present invention relates to the preparation of 5-substitutedimidazole compounds which have farnesyl tranferase inhibitory activityand which are also useful as intermediates for the preparation of otherimidazole compounds having such activity.

[0002] Oncogenes frequently encode protein components of signaltransduction pathways which lead to stimulation of cell growth andmitogenesis. Oncogene expression in cultured cells leads to cellulartransformation, characterized by the ability of cells to grow in softagar and the growth of cells as dense foci lacking the contactinhibition exhibited by non-transformed cells. Mutation and/oroverexpression of certain oncogenes is frequently associated with humancancer. A particular group of oncogenes is known as ras which have beenidentified in mammals, birds, insects, mollusks, plants, fungi andyeasts. The family of mammalian ras oncogenes consists of three majormembers (“isoforms”): H-ras, K-ras and N-ras oncogenes. These rasoncogenes code for highly related proteins generically known asp21^(ras). Once attached to plasma membranes, the mutant or oncogenicforms of p2^(ras) will provide a signal for the transformation anduncontrolled growth of malignant tumor cells. To acquire thistransforming potential, the precursor of the p21^(ras) oncoprotein mustundergo an enzymatically catalyzed farnesylation of the cysteine residuelocated in a carboxyl-terminal tetrapeptide. Therefore, inhibitors ofthe enzymes that catalyzes this modification, i.e. farnesyl transferase,will prevent the membrane attachment of p21^(ras) and block the aberrantgrowth of ras-transformed tumors. Hence, it is generally accepted in theart that farnesyl transferase inhibitors can be very useful asanticancer agents for tumors in which ras contributes to transformation.

[0003] In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, thereare described 2quinolone derivatives which exhibit farnesyl transferaseinhibiting activity. WO 00/39082 describes a class of novel1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linkedimidazole, which show farnesyl protein transferase and geranylgeranyltransferase inhibiting activity. Other quinolone compounds havingfarnesyl transferase inhibiting activity are described in WO 00/12498,00/12499 and 00/47574. A particular compound described in theabove-mentioned WO 97/21701, namely(R)-(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]4-(3-chlorophenyl)-1-methyl-2(1H)quinolinone,has been found to have very potent activity against neoplastic diseasesand is currently the subject of clinical trials to determine the extentof its therapeutic effect against various cancers. The absolutestereochemical configuration of the compound was not determined in theexperiments described in the above-mentioned patent specification, butthe compound was identified by the prefix “(B)” to indicate that it wasthe second compound isolated from column chromatography. The compoundthus obtained has been found to have the (R)-(+)-configuration. Thiscompound, which will be referred to below by its published code numberR115777, has the following formula (I):—

[0004] The preparation of R115777 is described in WO97/21701 by asynthetic route which includes the key step of introducing the 1-methylimidazolyl group into a corresponding oxo compound as shown below:

[0005] As described in Example B1 of the above patent specification,1-methyl imidazole in tetrahydrofuran is mixed with a solution ofn-butyllithium in a hexane solvent to which is addedchlorotriethylsilane (triethylsilyl chloride), followed by a furtheraddition of n-butyllithium in hexane, the resulting mixture being cooledto −78° C. before the addition of a solution of compound (II) intetrahydrofuran. The reaction mixture is subsequently brought to roomtemperature, and then hydrolysed, extracted with ethyl acetate and theorganic layer worked up to obtain the desired product resulting in a 52%yield of the compound (III). The latter compound can then be convertedinto R115777 as described in WO97/21701.

[0006] In order to ensure an economical supply of R115777 fordevelopment purposes and marketing, an efficient synthetic process forthe production of R115777 is required. However, the procedure describedin WO97/21701 above for converting compound (II) to compound (III) has anumber of disadvantages. For example, the procedure results in theundesired formation of a corresponding compound in which the imidazolering is attached to the remainder of the molecule at the 2-position ofthe ring instead of the desired 5-position in R 15777. In order toobtain an economic production of the desired 5-isomer, it is importantto reduce the formation of the undesired 2-isomer, and on a commercialscale, even such a reduction by say one or two percentage pointsrepresents an important desideratum. Also there is significant formationof other impurities in the final product, for example the correspondingbis-imidazole compound. The use of n-butyllithium is also undesirable ina commercial process in view of its pyrophoric nature and the formationof butane, a flammable gas, as the by-product. Finally, the carrying outof the process at a temperature as low as −78° C. is inconvenient andcostly on a commercial scale in view of the specialised equipmentrequired to perform a large scale process at such low temperature. Thereis therefore a need to improve the above reaction step whereby it can becarried out in an efficient and economical manner on a commercial scale.

[0007] It is an object of the present invention to provide a new andimproved process for the preparation of the compound (III) from compound(II) in an improved yield of the former compound while minimising theformation of undesired isomers and under conditions which provideeconomic advantages for operation on a commercial scale. We have nowfound that such improvements in yield, impurity profile and commercialease of operation can be achieved by the use of n-hexyllithium in placeof n-butyllithium and the use of triisobutylsilyl chloride in place oftriethylsilyl chloride, with particularly advantageous results obtainedby the use of a temperature of at least −40° C.

[0008] According to one feature of the present invention therefore weprovide a process for the preparation of a compound (III), i.e.4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,and its pharmaceutically acceptable salts:

[0009] which comprises reacting a compound of formula (II), i.e.6-(4-chlorobenzoyl)4(3-chlorophenyl)-1-methyl-2(1H)quinolinone:

[0010] with a C₆₋₈alkyllithium compound, 1-methylimidazole and atri(C₄₋₆alkyl)silyl halide.

[0011] The C₆₋₈alkyllithium compound is preferably a hexyllithiumcompound especially n-hexyllithium. The tri(C₄₋₆alkyl)silyl halide ispreferably a tributylsilyl halide especially tri-iso-butylsilyl halide.The silyl halide is preferably a silyl chloride.

[0012] The above reaction is generally carried out at a temperature ofat least −40° C., preferably at least −20° C., and preferably −5 to +5°C., especially about 0° C., the higher temperatures providing animproved C5-/C2-isomer ratio, i.e. the ratio between the compound inwhich the imidazolyl group is attached to the remainder of the moleculeat the C5-position and the corresponding compound attached at theC2-position. This selectivity at such relatively high temperatures isremarkable in view of suggestions in the literature that the silyl groupis unsuitable as a blocking group, due to the 2- to 5-position migrationof 2-(trialkylsilyl)-substituted 5-lithio-1-methylimidazoles (G. Shapiroand M. Marzi, Tetrahedron Letters, Vol. 34, No. 21, pp 3401-3404, 1993;G. Shapiro and B. Gomez-Lor, J. Organic Chemistry, Vol. 59, pp5524-5526, 1994).

[0013] The reaction is conveniently effected in an ethereal organicsolvent, for example diethyl ether, tert-butyl methyl ether or morepreferably tetrahydrofuran.

[0014] In more detail, the reaction may be conveniently effected byinitially preparing a solution of 1-methylimidazole in a solvent such astetrahydrofuran, to which is added a portion of the hexyllithium in asolvent such as n-hexane. The silyl halide is then added to theresulting reaction mixture, and a further portion of the hexyllithium ina solvent such as n-hexane is also added. The compound of formula (II)in a solvent such as tetrahydrofuran is then added to the reactionmixture, keeping the temperature between −5° C. and 0° C.

[0015] The resulting product of formula (III) can be convenientlyisolated by crystallisation as a base, or by salt formation. Afterconcentration of the reaction mixture, a suitable solvent, preferablyiso-propyl acetate, is added to the residue and precipitation of theproduct results. For salt formation, hydrochloric acid gas, orhydrochloric acid solution in preferably 2-propanol, is added directlyto the reaction mixture in tetrahydrofuran resulting in precipitation ofthe salt. Alternatively, hydrochloric acid is added to a solution of thereaction residue in a suitable solvent, preferably acetone, resulting inprecipitation of the salt. The resulting compound of formula (III) canbe subsequently converted into R115777 for example as described inWO97/21701, or more particularly as described below.

[0016] Thus, for example the compound of formula (III) can bechlorinated to form the following compound of formula (I), i.e.4-(3-chlorophenyl)-6-[chloro-(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone:

[0017] The above chlorination reaction can be effected for example bytreatment of the compound of formula (III) with thionyl chloride orphosphorus trichloride, in an inert solvent, e.g. toluene,N,N-dimethylacetamide or, more preferably, N,N-dimethylimidazolidinone,for example at a temperature of from 0° C. to the reflux temperature ofthe reaction mixture, preferably at room temperature. The chlorocompound of formula (IV) can then be treated, conveniently in situwithout the need to isolate the compound, with an aminating agent toform the following amino compound of formula (V), i.e.6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1-H)-quinolinone:

[0018] The amination reaction can be conveniently effected by treatmentof the compound of formula (IV) with ammonia gas or a solution ofammonia in a suitable solvent, preferably methanol, the reaction beinggenerally effected in an inert solvent e.g. toluene, or by the additionof ammonia to a solution of compound (IV) in N,N-dimethylacetamide orpreferably N,N-dimethylimidazolidinone. The reaction is effected forexample at a temperature of 0° to 40° C., preferably at roomtemperature. If the solvent is

[0019] N,N-dimethylimidazolidinone, the resulting compound is isolatedby the addition of water, resulting in precipitation of compound (V)which can then be filtered, washed with water and dried. The compound offormula (V) is obtained in an unresolved form and can be separated intoits constituent enantiomers in conventional manner, for example bytreatment with a chiral acid to form the respective diastereomeric saltswhich can then be separated and the salt having the desiredR-configuration converted to the corresponding R115777 parent compound.Thus for example, the compound can be reacted with L-(−)-dibenzoyltartaric acid (DBTA) to form the diastereomeric tartrate salt which istreated with a base, preferably aqueous ammonium hydroxide, to form thecrude (R)-(+) R115777 which is then purified by recrystallisation fromethanol. The above intermediate tartrate salt, i.e.R-(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone[R—(R*,R*)]-2,3-bis(benzoyloxy)butanedioate (2:3), is a new compound andrepresents a further feature of the invention. The resulting (R)-(+)R115777 can be used for the therapeutic treatment of cancers asdescribed in WO 97/21701. The starting compound of formula (II), whichis employed in the process according to the invention, can be preparedas described in WO 97/21701.

[0020] The following Examples illustrate the present invention.

[0021] Preparation of compound (III):

[0022] 110 ml of dry tetaahydrofuran was added to 7.6 ml of1-methylimidazole (0.0946 mole) and the resulting solution cooled to−15° C.37.8 ml of n-hexyllithium 2.5 M in n-hexane (0.0946 mole) wasadded, while the temperature during addition was kept between −5° C. and0° C. After addition, the reaction mixture was stirred for 15 minutes,while cooling to −12° C. 26.2 ml of tri-iso-butylsilyl chloride (0.0964mole) was added, while the temperature during addition was kept between−5° and 0° C. After addition, the reaction mixture was stirred for 15minutes, while cooling to −13° C. 37.2 ml of n-hexyllithium 2.5 M inn-hexane (0.0930 mole) was added, while the temperature during additionwas kept between −5° C. and 0° C. (some precipitation occured). Afteraddition, the reaction mixture was stirred for 15 minutes, while coolingto −14° C. 128 ml of dry tetrahydrofuran was added to 26.22 g of64-chlorobenzoyl)₄-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (compound(II)) (0.0642 mole) and stirred until dissolution. This solution wasadded to the reaction mixture, while the temperature during addition waskept between −5° C. and 0° C. After addition, the reaction mixture wasstirred for 15 minutes between −5° C. and 0° C. 128 ml of water wasadded to the reaction mixture, followed by the addition of 10.6 ml ofacetic acid. The mixture was then heated to 40° C. and stirred for 2hours. The layers were separated and the organic layer washed with 32 mlwater. 64 ml water and 7.8 ml aqueous NaOH 50% were added to the organiclayer which was stirred for 1 hour at ambient temperature. The layerswere separated and the organic layer concentrated under reducedpressure, yielding 51.08 g of a brown oil (46.6 wt %4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone(compound III); 75.6% yield).

[0023] The product can be isolated via the procedures mentioned above.The resulting product was analysed by hplc using the followingconditions:—

[0024] Column: Hypersil C18-BD 3 μm, 100 mm×4 mm (i.d.)

[0025] Mobile Phase:

[0026] Solvent A: 0.5% NH₄OAc Solvent B: CH₃CN Gradient: Time % A % B 0100 0 15 0 100 18 0 100 19 100 0 23 100 0

[0027] Detector: UV 254 nm

[0028] Solvent: DMF

[0029] The product was found to have a C5:C2 ratio of 99.8:0.2. Incontrast using n-butyllithium in place of n-hexyllithium, triethylsilylchloride in place of tri-iso-butylsilyl chloride and conducting theprocess at −70° C., i.e. generally in accordance with prior artprocedures discussed above, the resulting product had a C5:C2 ratio of95:5, a significant difference in commercial terms.

[0030] Preparation of Compound (IV)

[0031] A 1 liter reaction vessel was charged with 105.4 g of4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinonehydrochloric acid salt (compound (III) and 400 ml ofN,N-dimethylimidazolidinone added at 22° C. The mixture was stirredvigorously for 15 minutes at 22° C. and became homogeneous. 32.1 ml ofthionyl chloride was added over 10 minutes to the reaction mixture, thereaction temperature rising from 22° C. to 40° C. After addition of thethionyl chloride, the reaction mixture was cooled from 40° C. to 22° C.and stirred for three hours at the latter temperature to provide asolution of4-(3-chlorophenyl)-6-[chloro-(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone(compound (IV).

[0032] Preparation of Unresolved Compound (I)

[0033] 429 ml of ammonia in methanol 7N was cooled to 5° C. in a 3 literreaction vessel and the solution of compound (IV), obtained in theprevious stage, added, while stirring, over 10 minutes, with anexothermic reaction, the temperature rising from 5° C. to 37° C. Afterthe addition was complete, the reaction mixture was cooled to 22° C. andstirred for 20 hours. 1000 ml of water was then added over 20 minutes,the addition being slightly exothermic so the reaction mixture wascooled to keep the temperature below 30° C. The mixture was then stirredfor 22 hours at 22° C., the resulting precipitate filtered off and theprecipitate washed three times with 100 ml of water to provide a yieldof 70-75% of6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]4-4-(3-chlorophenyl)-1-methyl-2(1H)qinolinone.

[0034] Resolution of Compound (1)

[0035] a) A 3 liter reaction vessel was charged with 146.8 g of6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]4-(3-chlorophenyl)-1-methyl-2(1H)quinolinoneand 301.1 g of L-)-dibenzoyl-tartaric acid monohydrate, 1200 ml ofacetone was added and the reaction mixture stirred vigorously for 10minutes at 22° C. to form a solution which was seeded with 100 mg of thefinal tartrate salt product (obtained from previous screeningexperiments) and then stirred for 22 hours at 22° C. The resultingprecipitate was filtered off and the precipitate was washed twice with75 ml of acetone and the product dried at 50° C. in vacuo to yield 114.7g ofR-(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone)R—(R*,R*)—2,3-bis(benzoyloxy)butanedioate (2:3).

[0036] b) 41.08 g of the product of stage a) and 80 ml ethanol werestirred for 15 minutes at 22° C. 12.0 ml concentrated aqueous ammoniumhydroxide was added over 2 minutes, and the reaction mixture stirred for1 hour at 25° C. 160 ml water was added over 10 minutes at 25° C. andthe mixture heated to reflux and stirred at reflux for 1 hour. Thereaction mixture was then cooled to 20° C. and stirred for 16 hours at20° C. The product was filtered, washed twice with 8 ml water and driedat 50° C. in vacuo to yield 16.87 g of(R)-(+)-6-[amino(4-chloro-phenyl)(1-methyl-1H-imidazol-5-yl)methyl]4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(compound (I)).

[0037] Purification of Compound (I)

[0038] 265 ml of ethanol was added to 19.9 g of compound (I), obtainedas described in the previous stage, and the mixture warmed whilestirring to reflux temperature (78° C.) and then stirred at refluxtemperature for 15 minutes before cooling the solution to 75° C. 1.0 gof activated carbon (Norit A Supra) was then added to the mixture whichwas stirred at reflux temperature for 1 hour, filtered while warm andthe filter then washed with 20 ml warm ethanol. The filtrate and washsolvent were combined (the product spontaneously crystallizes at 48°C.), and the mixture warmed to reflux temperature and concentrated byremoving 203 ml of ethanol. The resulting suspension was cooled to 22°C., stirred for 18 hours at 22° C., cooled to 2° C. and stirred for 5more hours at 2° C. The precipitate was filtered and washed with 4 mlethanol and the product dried at 50° c in vacuo to yield 17.25 g ofpurified compound (I) which complies with the infrared spectrum ofreference material.

1. A process for the preparation of4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)uinolinone(III) and its pharmaceutically acceptable salts:

which comprises reacting6-(4-chlorobenzoyl)-4-3-chlorophenyl)-1-methyl-2(1H)-quinolinone (II):

with a C₆₋₈alkyllithium compound, 1-methylimidazole and atri(C₄₋₆allyl)silyl halide.
 2. A process as claimed in claim 1 in whichthe C₆₋₈alktllithium compound is a hexyllithium compound.
 3. A processas claimed in claim 2 in which the hexyllithium compound isn-hexyllithium.
 4. A process as claimed in any of the preceding claimsin which the tri(C4 alkyl)silyl halide is a tributylsilyl halide.
 5. Aprocess as claimed in claim 4 in which the tributylsilyl halide is atri-iso-butylsilyl halide.
 6. A process as claimed in any of thepreceding claims in which the tri(C₄₋₆alkyl)silyl halide is atri(C₄₋₆alkyl)silyl chloride.
 7. A process as claimed in any of thepreceding claims in which the reaction is effected at a temperature ofat least −40° C.
 8. A process as claimed in claim 7 in which thereaction is effected at a temperature of at least −20° C.
 9. A processas claimed in claim 8 in which the reaction is effected at a temperatureof −5 to +5° C.
 10. A process as claimed in any of the preceding claimsin which the resulting compound (III) is subsequently used asintermediate for the preparation of(R)-(+)-6-[amino(4-chloro-phenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.